Prediction of pKa Using Machine Learning Methods with Rooted Topological Torsion Fingerprints: Application to Aliphatic Amines.

The acid-base dissociation constant, pKa, is a key parameter to define the ionization state of a compound and directly affects its biopharmaceutical profile. In this study, we developed a novel approach for pKa prediction using rooted topological torsion fingerprints in combination with five machine learning (ML) methods: random forest, partial least squares, extreme gradient boosting, lasso regression, and support vector regression. With a large and diverse set of 14 499 experimental pKa values, pKa models were developed for aliphatic amines. The models demonstrated consistently good prediction statistics and were able to generate accurate prospective predictions as validated with an external test set of 726 pKa values (RMSE 0.45, MAE 0.33, and R2 0.84 by the top model). The factors that may affect prediction accuracy and model applicability were carefully assessed. The results demonstrated that rooted topological torsion fingerprints coupled with ML methods provide a promising approach for developing accurate pKa prediction models.

Biased Complement Diversity Selection for Effective Exploration of Chemical Space in Hit-Finding Campaigns.

The success of hit-finding campaigns relies on many factors, including the quality and diversity of the set of compounds that is selected for screening. This paper presents a generalized workflow that guides compound selections from large compound archives with opportunities to bias the selections with available knowledge in order to improve hit quality while still effectively sampling the accessible chemical space. An optional flag in the workflow supports an explicit complement design function where diversity selections complement a given core set of compounds. Results from three project applications as well as a literature case study exemplify the effectiveness of the approach, which is available as a KNIME workflow named Biased Complement Diversity (BCD).

Design and synthesis of potent RSK inhibitors.

Utilizing the already described 3,4-bi-aryl pyridine series as a starting point, incorporation of a second ring system with a hydrogen bond donor and additional hydrophobic contacts yielded the azaindole series which exhibited potent, picomolar RSK2 inhibition and the most potent in vitro target modulation seen thus far for a RSK inhibitor. In the context of the more potent core, several changes at the phenol moiety were assessed to potentially find a tool molecule appropriate for in vivo evaluation.

Optimization of novel monobactams with activity against carbapenem-resistant Enterobacteriaceae - Identification of LYS228.

Metallo-ß-lactamases (MBLs), such as New Delhi metallo-ß-lactamase (NDM-1) have spread world-wide and present a serious threat. Expression of MBLs confers resistance in Gram-negative bacteria to all classes of ß-lactam antibiotics, with the exception of monobactams, which are intrinsically stable to MBLs. However, existing first generation monobactam drugs like aztreonam have limited clinical utility against MBL-expressing strains because they are impacted by serine ß-lactamases (SBLs), which are often co-expressed in clinical isolates. Here, we optimized novel monobactams for stability against SBLs, which led to the identification of LYS228 (compound 31). LYS228 is potent in the presence of all classes of ß-lactamases and shows potent activity against carbapenem-resistant isolates of Enterobacteriaceae (CRE).

Design, synthesis and structure activity relationship of potent pan-PIM kinase inhibitors derived from the pyridyl carboxamide scaffold.

The Pim proteins (1, 2 and 3) are serine/threonine kinases that have been found to be upregulated in many hematological malignancies and solid tumors. As a result of overlapping functions among the three isoforms, inhibition of all three Pim kinases has become an attractive strategy for cancer therapy. Herein we describe our efforts in identifying potent pan-PIM inhibitors that are derived from our previously reported pyridyl carboxamide scaffold as part of a medicinal chemistry strategy to address metabolic stability.

Ligand efficient tetrahydro-pyrazolopyridines as inhibitors of ERK2 kinase.

A series of structure based drug design hypotheses and focused screening efforts drove improvements in the potency and lipophilic efficiency of tetrahydro-pyrazolopyridine based ERK2 inhibitors. Elaboration of a fragment chemical lead established a new lipophilic aryl-Tyr interaction resulting in a substantial potency improvement. Subsequent cleavage of the lipophilic moiety led to reconfiguration of the ligand bound binding cleft. The reconfiguration established a polar contact between a newly liberated N-H and a vicinal Asp, resulting in further improvements in lipophilic efficiency and in vitro clearance.

FOCUS--Development of a Global Communication and Modeling Platform for Applied and Computational Medicinal Chemists.

Communication of data and ideas within a medicinal chemistry project on a global as well as local level is a crucial aspect in the drug design cycle. Over a time frame of eight years, we built and optimized FOCUS, a platform to produce, visualize, and share information on various aspects of a drug discovery project such as cheminformatics, data analysis, structural information, and design. FOCUS is tightly integrated with internal services that involve-among others-data retrieval systems and in-silico models and provides easy access to automated modeling procedures such as pharmacophore searches, R-group analysis, and similarity searches. In addition, an interactive 3D editor was developed to assist users in the generation and docking of close analogues of a known lead. In this paper, we will specifically concentrate on issues we faced during development, deployment, and maintenance of the software and how we continually adapted the software in order to improve usability. We will provide usage examples to highlight the functionality as well as limitations of FOCUS at the various stages of the development process. We aim to make the discussion as independent of the software platform as possible, so that our experiences can be of more general value to the drug discovery community.

2-Amino-7-substituted benzoxazole analogs as potent RSK2 inhibitors.

2-Amino-7-substituted benzoxazole analogs were identified by HTS as inhibitors of RSK2. Molecular modeling and medicinal chemistry techniques were employed to explore the SAR for this series with a focus of improving in vitro and target modulation potency and physicochemical properties.

Discovery of novel 3,5-disubstituted indole derivatives as potent inhibitors of Pim-1, Pim-2, and Pim-3 protein kinases.

A series of novel 3,5-disubstituted indole derivatives as potent and selective inhibitors of all three members of the Pim kinase family is described. High throughput screen identified a pan-Pim kinase inhibitor with a promiscuous scaffold. Guided by structure-based drug design, SAR of the series afforded a highly selective indole chemotype that was further developed into a potent set of compounds against Pim-1, 2, and 3 (Pim-1 and Pim-3: IC(50)≤2nM and Pim-2: IC(50)≤100nM).

Towards the sustainable discovery and development of new antibiotics.

An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.

Towards the sustainable discovery and development of new antibiotics.

An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.

Pyrazolopyridines as potent PDE4B inhibitors: 5-heterocycle SAR.

Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-α production from isolated human peripheral blood mononuclear cells.

An Artificial Intelligence Approach to Proactively Inspire Drug Discovery with Recommendations.

Artificial intelligence (AI) is becoming established in drug discovery. For example, many in the industry are applying machine learning approaches to target discovery or to optimize compound synthesis. While our organization is certainly applying these sorts of approaches, we propose an additional approach: using AI to augment human intelligence. We have been working on a series of recommendation systems that take advantage of our existing laboratory processes, both wet and computational, in order to provide inspiration to our chemists, suggest next steps in their work, and automate existing workflows. We will describe five such systems in various stages of deployment within the Novartis Institutes for BioMedical Research. While each of these systems addresses different stages of the discovery pipeline, all of them share three common features: a trigger that initiates the recommendation, an analysis that leverages our existing systems with AI, and the delivery of a recommendation. The goal of all of these systems is to inspire and accelerate the drug discovery process.

Synthesis and Structure-Activity Relationship of Tetra-Substituted Cyclohexyl Diol Inhibitors of Proviral Insertion of Moloney Virus (PIM) Kinases.

Overexpression of PIM 1, 2, and 3 kinases is frequently observed in many malignancies. Previously, we discovered a potent and selective pan-PIM kinase inhibitor, compound 2, currently in phase I clinical trials. In this work, we were interested in replacing the amino group on the cyclohexane ring in compound 2 with a hydroxyl group. Structure-based drug design led to cellularly potent but metabolically unstable tetra-substituted cyclohexyl diols. Efforts on the reduction of Log D by introducing polar heterocycles improved metabolic stability. Incorporating fluorine to the tetra-substituted cyclohexyl diol moiety further reduced Log D, resulting in compound 14, a cellularly potent tetra-substituted cyclohexyl diol inhibitor with moderate metabolic stability and good permeability. We also describe the development of efficient and scalable synthetic routes toward synthetically challenging tetra-substituted cyclohexyl diol compounds. In particular, intermediate 36 was identified as a versatile intermediate, enabling a large-scale synthesis of highly substituted cyclohexane derivatives.

Quinolines as a novel structural class of potent and selective PDE4 inhibitors: optimisation for oral administration.

Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD.

Size Matters and How You Measure It: A Gram-Negative Antibacterial Example Exceeding Typical Molecular Weight Limits.

Monobactam antibiotic 1 is active against Gram-negative bacteria even though it has a higher molecular weight (MW) than the limit of 600 Da typically applied in designing such compounds. On the basis of 2D NMR data, the compound is able to adopt a compact conformation. The dimensions, projection area, and dipole moment derived from this conformation are compatible with porin permeation, as are locations of polar groups upon superimposition to the crystal structure of ampicillin bound to E. coli OmpF porin. Minimum inhibitory concentration (MIC) shifts in a porin knock-out strain are also consistent with 1 predominately permeating through porins. In conclusion, we describe a carefully characterized case of a molecule outside default design parameters where MW does not adequately represent the 3D shape more directly related to permeability. Leveraging 3D design criteria would open up additional chemical space currently underutilized due to limitations perceived in 2D.

4-(1H-indazol-5-yl)-6-phenylpyrimidin-2(1H)-one analogs as potent CDC7 inhibitors.

A series of 4-(4-hydroxyphenyl)-6-phenylpyrimidin-2(1H)-ones were identified by HTS as inhibitors of CDC7. Molecular modeling and medicinal chemistry techniques were employed to explore the SAR for this series with a focus on removing potential metabolic liabilities and improving cellular potency.

Pyrazolopyridines as a novel structural class of potent and selective PDE4 inhibitors.

Optimisation of a high-throughput screening hit resulted in the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective inhibitors of Phosphodiesterase 4 (PDE4). Herein, we describe early SAR studies around this novel template highlighting preferred substituents and rationalization of SAR through X-ray crystal structures of analogues bound to the PDE4 active site. Pyrazolopyridine 20a was found to be a potent and selective PDE4 inhibitor which also inhibits LPS induced TNF-alpha production from isolated human peripheral blood mononuclear cells and has an encouraging rat PK profile suitable for oral dosing.

Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria.

The discovery and development of new antibiotics capable of curing infections due to multidrug-resistant and pandrug-resistant Gram-negative bacteria are a major challenge with fundamental importance to our global healthcare system. Part of our broad program at Novartis to address this urgent, unmet need includes the search for new agents that inhibit novel bacterial targets. Here we report the discovery and hit-to-lead optimization of new inhibitors of phosphopantetheine adenylyltransferase (PPAT) from Gram-negative bacteria. Utilizing a fragment-based screening approach, we discovered a number of unique scaffolds capable of interacting with the pantetheine site of E. coli PPAT and inhibiting enzymatic activity, including triazolopyrimidinone 6. Structure-based optimization resulted in the identification of two lead compounds as selective, small molecule inhibitors of bacterial PPAT: triazolopyrimidinone 53 and azabenzimidazole 54 efficiently inhibited E. coli and P. aeruginosa PPAT and displayed modest cellular potency against the efflux-deficient E. coli Δ tolC mutant strain.

Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase.

PRC2 is a multisubunit methyltransferase involved in epigenetic regulation of early embryonic development and cell growth. The catalytic subunit EZH2 methylates primarily lysine 27 of histone H3, leading to chromatin compaction and repression of tumor suppressor genes. Inhibiting this activity by small molecules targeting EZH2 was shown to result in antitumor efficacy. Here, we describe the optimization of a chemical series representing a new class of PRC2 inhibitors which acts allosterically via the trimethyllysine pocket of the noncatalytic EED subunit. Deconstruction of a larger and complex screening hit to a simple fragment-sized molecule followed by structure-guided regrowth and careful property modulation were employed to yield compounds which achieve submicromolar inhibition in functional assays and cellular activity. The resulting molecules can serve as a simplified entry point for lead optimization and can be utilized to study this new mechanism of PRC2 inhibition and the associated biology in detail.